Chapter 19 : Enterohemorrhagic Pathogenesis and the Host Response

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Bacterial exotoxins may cause damage to host cells by defined mechanisms. Depending on the presence of the globotriaosylceramide (Gb3) receptor, Shiga toxin may bind to cells and induce the ribotoxic stress response and apoptosis ( ). The toxin can also induce a proinflammatory response in cells, an effect that may be dissociated from ribosome inactivation and can even occur in cells lacking protein synthesis machinery. Bacterial lipopolysaccharide (LPS) induces a host response by binding to Toll-like receptor 4 (TLR4) and activating specific intracellular pathways. The activation of proinflammatory pathways, if excessive, promotes damage to the host. This article addresses enterohemorrhagic (EHEC) pathogenesis and the host response, examining the innate and adaptive immune responses to the bacteria and virulence factors and how they affect the process of colonization, transfer and transport of virulence factors in the circulation, activation of thrombosis and inflammation, and specific end-organ damage to the kidney and the brain.

Citation: Karpman D, Ståhl A. 2015. Enterohemorrhagic Pathogenesis and the Host Response, p 403-417. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0009-2013
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1. Tesh VL . 2012. The induction of apoptosis by Shiga toxins and ricin. Curr Top Microbiol Immunol 357 : 137 178.[PubMed] [CrossRef]
2. Jandhyala DM,, Thorpe CM,, Magun B . 2012. Ricin and Shiga toxins: effects on host cell signal transduction. Curr Top Microbiol Immunol 357 : 41 65.[PubMed] [CrossRef]
3. Chromek M,, Arvidsson I,, Karpman D . 2012. The antimicrobial peptide cathelicidin protects mice from Escherichia coli O157:H7-mediated disease. PLoS One 7 : e46476. [PubMed] [CrossRef]
4. House B,, Kus JV,, Prayitno N,, Mair R,, Que L,, Chingcuanco F,, Gannon V,, Cvitkovitch DG,, Barnett Foster D . 2009. Acid-stress-induced changes in enterohaemorrhagic Escherichia coli O157 : H7 virulence. Microbiology 155 : 2907 2918.[PubMed] [CrossRef]
5. Foster JW . 2004. Escherichia coli acid resistance: tales of an amateur acidophile. Nat Rev Microbiol 2 : 898 907.[PubMed] [CrossRef]
6. Barnett Foster D . 2013. Modulation of the enterohemorrhagic E. coli virulence program through the human gastrointestinal tract. Virulence 4 : 315 323.[PubMed] [CrossRef]
7. Phillips AD,, Navabpour S,, Hicks S,, Dougan G,, Wallis T,, Frankel G . 2000. Enterohaemorrhagic Escherichia coli O157:H7 target Peyer’s patches in humans and cause attaching/effacing lesions in both human and bovine intestine. Gut 47 : 377 381.[PubMed] [CrossRef]
8. Chong Y,, Fitzhenry R,, Heuschkel R,, Torrente F,, Frankel G,, Phillips AD . 2007. Human intestinal tissue tropism in Escherichia coli O157:H7—initial colonization of terminal ileum and Peyer’s patches and minimal colonic adhesion ex vivo. Microbiology 153 : 794 802.[PubMed] [CrossRef]
9. Etienne-Mesmin L,, Chassaing B,, Sauvanet P,, Denizot J,, Blanquet-Diot S,, Darfeuille-Michaud A,, Pradel N,, Livrelli V . 2011. Interactions with M cells and macrophages as key steps in the pathogenesis of enterohemorrhagic Escherichia coli infections. PLoS One 6 : e23594. [PubMed] [CrossRef]
10. Miller TL,, Wolin MJ . 1996. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl Environ Microbiol 62 : 1589 1592.[PubMed]
11. Nakanishi N,, Tashiro K,, Kuhara S,, Hayashi T,, Sugimoto N,, Tobe T . 2009. Regulation of virulence by butyrate sensing in enterohaemorrhagic Escherichia coli . Microbiology 155 : 521 530.[PubMed] [CrossRef]
12. Herold S,, Paton JC,, Srimanote P,, Paton AW . 2009. Differential effects of short-chain fatty acids and iron on expression of iha in Shiga-toxigenic Escherichia coli . Microbiology 155 : 3554 3563.[PubMed] [CrossRef]
13. Jacewicz MS,, Acheson DW,, Mobassaleh M,, Donohue-Rolfe A,, Balasubramanian KA,, Keusch GT . 1995. Maturational regulation of globotriaosylceramide, the Shiga-like toxin 1 receptor, in cultured human gut epithelial cells. J Clin Invest 96 : 1328 1335.[PubMed] [CrossRef]
14. Schauber J,, Svanholm C,, Termen S,, Iffland K,, Menzel T,, Scheppach W,, Melcher R,, Agerberth B,, Luhrs H,, Gudmundsson GH . 2003. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52 : 735 741.[PubMed] [CrossRef]
15. Iimura M,, Gallo RL,, Hase K,, Miyamoto Y,, Eckmann L,, Kagnoff MF . 2005. Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol 174 : 4901 4907.[PubMed] [CrossRef]
16. Islam D,, Bandholtz L,, Nilsson J,, Wigzell H,, Christensson B,, Agerberth B,, Gudmundsson G . 2001. Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 7 : 180 185.[PubMed] [CrossRef]
17. Pacheco AR,, Sperandio V . 2009. Inter-kingdom signaling: chemical language between bacteria and host. Curr Opin Microbiol 12 : 192 198.[PubMed] [CrossRef]
18. Hughes DT,, Clarke MB,, Yamamoto K,, Rasko DA,, Sperandio V . 2009. The QseC adrenergic signaling cascade in enterohemorrhagic E. coli (EHEC). PLoS Pathog 5 : e1000553. [PubMed] [CrossRef]
19. Malyukova I,, Murray KF,, Zhu C,, Boedeker E,, Kane A,, Patterson K,, Peterson JR,, Donowitz M,, Kovbasnjuk O . 2009. Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am J Physiol Gastrointest Liver Physiol 296 : G78 G92.[PubMed] [CrossRef]
20. Zumbrun SD,, Hanson L,, Sinclair JF,, Freedy J,, Melton-Celsa AR,, Rodriguez-Canales J,, Hanson JC,, O’Brien AD . 2010. Human intestinal tissue and cultured colonic cells contain globotriaosylceramide synthase mRNA and the alternate Shiga toxin receptor globotetraosylceramide. Infect Immun 78 : 4488 4499.[PubMed] [CrossRef]
21. Schüller S,, Heuschkel R,, Torrente F,, Kaper JB,, Phillips AD . 2007. Shiga toxin binding in normal and inflamed human intestinal mucosa. Microbes Infect 9 : 35 39.[PubMed] [CrossRef]
22. Bell CJ,, Elliott EJ,, Wallace JL,, Redmond DM,, Payne J,, Li Z,, O’Loughlin EV . 2000. Do eicosanoids cause colonic dysfunction in experimental E. coli O157:H7 (EHEC) infection? Gut 46 : 806 812.[PubMed] [CrossRef]
23. Smith WE,, Kane AV,, Campbell ST,, Acheson DW,, Cochran BH,, Thorpe CM . 2003. Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. Infect Immun 71 : 1497 1504.[PubMed] [CrossRef]
24. Schüller S,, Frankel G,, Phillips AD . 2004. Interaction of Shiga toxin from Escherichia coli with human intestinal epithelial cell lines and explants: Stx2 induces epithelial damage in organ culture. Cell Microbiol 6 : 289 301.[PubMed] [CrossRef]
25. Barnett Foster D,, Abul-Milh M,, Huesca M,, Lingwood CA . 2000. Enterohemorrhagic Escherichia coli induces apoptosis which augments bacterial binding and phosphatidylethanolamine exposure on the plasma membrane outer leaflet. Infect Immun 68 : 3108 3115.[PubMed] [CrossRef]
26. Kashiwamura M,, Kurohane K,, Tanikawa T,, Deguchi A,, Miyamoto D,, Imai Y . 2009. Shiga toxin kills epithelial cells isolated from distal but not proximal part of mouse colon. Biol Pharm Bull 32 : 1614 1617.[PubMed] [CrossRef]
27. Keenan KP,, Sharpnack DD,, Collins H,, Formal SB,, O’Brien AD . 1986. Morphologic evaluation of the effects of Shiga toxin and E. coli Shiga-like toxin on the rabbit intestine. Am J Pathol 125 : 69 80.[PubMed]
28. Békássy ZD,, Calderon Toledo C,, Leoj G,, Kristoffersson A,, Leopold SR,, Perez MT,, Karpman D . 2011. Intestinal damage in enterohemorrhagic Escherichia coli infection. Pediatr Nephrol 26 : 2059 2071.[PubMed] [CrossRef]
29. Hurley BP,, Jacewicz M,, Thorpe CM,, Lincicome LL,, King AJ,, Keusch GT,, Acheson DW . 1999. Shiga toxins 1 and 2 translocate differently across polarized intestinal epithelial cells. Infect Immun 67 : 6670 6677.[PubMed]
30. Hurley BP,, Thorpe CM,, Acheson DW . 2001. Shiga toxin translocation across intestinal epithelial cells is enhanced by neutrophil transmigration. Infect Immun 69 : 6148 6155.[PubMed] [CrossRef]
31. Slutsker L,, Ries AA,, Greene KD,, Wells JG,, Hutwagner L,, Griffin PM . 1997. Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med 126 : 505 513.[PubMed] [CrossRef]
32. Jung HC,, Eckmann L,, Yang SK,, Panja A,, Fierer J,, Morzycka-Wroblewska E,, Kagnoff MF . 1995. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 95 : 55 65.[PubMed] [CrossRef]
33. Thorpe CM,, Hurley BP,, Lincicome LL,, Jacewicz MS,, Keusch GT,, Acheson DW . 1999. Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells. Infect Immun 67 : 5985 5993.[PubMed]
34. Thorpe CM,, Smith WE,, Hurley BP,, Acheson DW . 2001. Shiga toxins induce, superinduce, and stabilize a variety of C-X-C chemokine mRNAs in intestinal epithelial cells, resulting in increased chemokine expression. Infect Immun 69 : 6140 6147.[PubMed] [CrossRef]
35. Yamasaki C,, Natori Y,, Zeng XT,, Ohmura M,, Yamasaki S,, Takeda Y,, Natori Y . 1999. Induction of cytokines in a human colon epithelial cell line by Shiga toxin 1 (Stx1) and Stx2 but not by non-toxic mutant Stx1 which lacks N-glycosidase activity. FEBS Lett 442 : 231 234.[PubMed] [CrossRef]
36. Colpoys WE,, Cochran BH,, Carducci TM,, Thorpe CM . 2005. Shiga toxins activate translational regulation pathways in intestinal epithelial cells. Cell Signal 17 : 891 899.[PubMed] [CrossRef]
37. Tesh VL,, Ramegowda B,, Samuel JE . 1994. Purified Shiga-like toxins induce expression of proinflammatory cytokines from murine peritoneal macrophages. Infect Immun 62 : 5085 5094.[PubMed]
38. Farfan MJ,, Cantero L,, Vergara A,, Vidal R,, Torres AG . 2013. The long polar fimbriae of STEC O157:H7 induce expression of pro-inflammatory markers by intestinal epithelial cells. Vet Immunol Immunopathol 152 : 126 131.[PubMed] [CrossRef]
39. Bellmeyer A,, Cotton C,, Kanteti R,, Koutsouris A,, Viswanathan VK,, Hecht G . 2009. Enterohemorrhagic Escherichia coli suppresses inflammatory response to cytokines and its own toxin. Am J Physiol Gastrointest Liver Physiol 297 : G576 G581.[PubMed] [CrossRef]
40. Ho NK,, Ossa JC,, Silphaduang U,, Johnson R,, Johnson-Henry KC,, Sherman PM . 2012. Enterohemorrhagic Escherichia coli O157:H7 Shiga toxins inhibit gamma interferon-mediated cellular activation. Infect Immun 80 : 2307 2315.[PubMed] [CrossRef]
41. Karpman D,, Connell H,, Svensson M,, Scheutz F,, Alm P,, Svanborg C . 1997. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection. J Infect Dis 175 : 611 620.[PubMed] [CrossRef]
42. Takeda K,, Akira S . 2004. TLR signaling pathways. Semin Immunol 16 : 3 9.[CrossRef]
43. Moresco EM,, LaVine D,, Beutler B . 2011. Toll-like receptors. Curr Biol 21 : R488 R493.[PubMed] [CrossRef]
44. Calderon Toledo C,, Rogers TJ,, Svensson M,, Tati R,, Fischer H,, Svanborg C,, Karpman D . 2008. Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7. Am J Pathol 173 : 1428 1439.[PubMed] [CrossRef]
45. Torgersen ML,, Engedal N,, Pedersen AM,, Husebye H,, Espevik T,, Sandvig K . 2011. Toll-like receptor 4 facilitates binding of Shiga toxin to colon carcinoma and primary umbilical vein endothelial cells. FEMS Immunol Med Microbiol 61 : 63 75.[PubMed] [CrossRef]
46. Carbonare CB,, Carbonare SB,, Carneiro-Sampaio MM . 2003. Early acquisition of serum and saliva antibodies reactive to enteropathogenic Escherichia coli virulence-associated proteins by infants living in an endemic area. Pediatr Allergy Immunol 14 : 222 228.[PubMed] [CrossRef]
47. Parissi-Crivelli A,, Parissi-Crivelli JM,, Giron JA . 2000. Recognition of enteropathogenic Escherichia coli virulence determinants by human colostrum and serum antibodies. J Clin Microbiol 38 : 2696 2700.[PubMed]
48. Karpman D,, Békássy ZD,, Sjögren AC,, Dubois MS,, Karmali MA,, Mascarenhas M,, Jarvis KG,, Gansheroff LJ,, O’Brien AD,, Arbus GS,, Kaper JB . 2002. Antibodies to intimin and Escherichia coli secreted proteins A and B in patients with enterohemorrhagic Escherichia coli infections. Pediatr Nephrol 17 : 201 211.[PubMed] [CrossRef]
49. Sjögren AC,, Kaper JB,, Caprioli A,, Karpman D . 2004. Enzyme-linked immunosorbent assay for detection of Shiga toxin-producing Escherichia coli infection by antibodies to Escherichia coli secreted protein B in children with hemolytic uremic syndrome. Eur J Clin Microbiol Infect Dis 23 : 208 211.[PubMed] [CrossRef]
50. Noguera-Obenza M,, Ochoa TJ,, Gomez HF,, Guerrero ML,, Herrera-Insua I,, Morrow AL,, Ruiz-Palacios G,, Pickering LK,, Guzman CA,, Cleary TG . 2003. Human milk secretory antibodies against attaching and effacing Escherichia coli antigens. Emerg Infect Dis 9 : 545 551.[CrossRef]
51. Loureiro I,, Frankel G,, Adu-Bobie J,, Dougan G,, Trabulsi LR,, Carneiro-Sampaio MM . 1998. Human colostrum contains IgA antibodies reactive to enteropathogenic Escherichia coli virulence-associated proteins: intimin, BfpA, EspA, and EspB. J Pediatr Gastroenterol Nutr 27 : 166 171.[PubMed] [CrossRef]
52. Palmeira P,, Carbonare SB,, Amaral JA,, Tino-De-Franco M,, Carneiro-Sampaio MM . 2005. Colostrum from healthy Brazilian women inhibits adhesion and contains IgA antibodies reactive with Shiga toxin-producing Escherichia coli . Eur J Pediatr 164 : 37 43.[PubMed] [CrossRef]
53. Bitzan M,, Moebius E,, Ludwig K,, Müller-Wiefel DE,, Heesemann J,, Karch H . 1991. High incidence of serum antibodies to Escherichia coli O157 lipopolysaccharide in children with hemolytic-uremic syndrome. J Pediatr 119 : 380 385.[PubMed] [CrossRef]
54. Ludwig K,, Grabhorn E,, Bitzan M,, Bobrowski C,, Kemper MJ,, Sobottka I,, Laufs R,, Karch H,, Müller-Wiefel DE . 2002. Saliva IgM and IgA are a sensitive indicator of the humoral immune response to Escherichia coli O157 lipopolysaccharide in children with enteropathic hemolytic uremic syndrome. Pediatr Res 52 : 307 313.[PubMed] [CrossRef]
55. Ludwig K,, Bitzan M,, Bobrowski C,, Müller-Wiefel DE . 2002. Escherichia coli O157 fails to induce a long-lasting lipopolysaccharide-specific, measurable humoral immune response in children with hemolytic-uremic syndrome. J Infect Dis 186 : 566 569.[PubMed] [CrossRef]
56. Palmeira P,, Yu Ito L,, Arslanian C,, Carneiro-Sampaio MM . 2007. Passive immunity acquisition of maternal anti-enterohemorrhagic Escherichia coli (EHEC) O157:H7 IgG antibodies by the newborn. Eur J Pediatr 166 : 413 419.[PubMed] [CrossRef]
57. Ludwig K,, Karmali MA,, Sarkim V,, Bobrowski C,, Petric M,, Karch H,, Muller-Wiefel DE . 2001. Antibody response to Shiga toxins Stx2 and Stx1 in children with enteropathic hemolytic-uremic syndrome. J Clin Microbiol 39 : 2272 2279.[PubMed] [CrossRef]
58. Ludwig K,, Sarkim V,, Bitzan M,, Karmali MA,, Bobrowski C,, Ruder H,, Laufs R,, Sobottka I,, Petric M,, Karch H,, Muller-Wiefel DE . 2002. Shiga toxin-producing Escherichia coli infection and antibodies against Stx2 and Stx1 in household contacts of children with enteropathic hemolytic-uremic syndrome. J Clin Microbiol 40 : 1773 1782.[PubMed] [CrossRef]
59. Martinez MB,, Taddei CR,, Ruiz-Tagle A,, Trabulsi LR,, Giron JA . 1999. Antibody response of children with enteropathogenic Escherichia coli infection to the bundle-forming pilus and locus of enterocyte effacement-encoded virulence determinants. J Infect Dis 179 : 269 274.[PubMed] [CrossRef]
60. Calderon Toledo C,, Arvidsson I,, Karpman D . 2011. Cross-reactive protection against enterohemorrhagic Escherichia coli infection by enteropathogenic E. coli in a mouse model. Infect Immun 79 : 2224 2233.[PubMed] [CrossRef]
61. Walters MD,, Matthei IU,, Kay R,, Dillon MJ,, Barratt TM . 1989. The polymorphonuclear leucocyte count in childhood haemolytic uraemic syndrome. Pediatr Nephrol 3 : 130 134.[PubMed] [CrossRef]
62. Robson WL,, Fick GH,, Wilson PC . 1988. Prognostic factors in typical postdiarrhea hemolytic-uremic syndrome. Child Nephrol Urol 9 : 203 207.[PubMed]
63. Fernandez GC,, Gomez SA,, Rubel CJ,, Bentancor LV,, Barrionuevo P,, Alduncin M,, Grimoldi I,, Exeni R,, Isturiz MA,, Palermo MS . 2005. Impaired neutrophils in children with the typical form of hemolytic uremic syndrome. Pediatr Nephrol 20 : 1306 1314.[PubMed] [CrossRef]
64. Milford D,, Taylor CM,, Rafaat F,, Halloran E,, Dawes J . 1989. Neutrophil elastases and haemolytic uraemic syndrome. Lancet 2 : 1153. [PubMed] [CrossRef]
65. Fitzpatrick MM,, Shah V,, Filler G,, Dillon MJ,, Barratt TM . 1992. Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma. Pediatr Nephrol 6 : 50 53.[PubMed] [CrossRef]
66. Hughes DA,, Smith GC,, Davidson JE,, Murphy AV,, Beattie TJ . 1996. The neutrophil oxidative burst in diarrhoea-associated haemolytic uraemic syndrome. Pediatr Nephrol 10 : 445 447.[PubMed] [CrossRef]
67. Forsyth KD,, Simpson AC,, Fitzpatrick MM,, Barratt TM,, Levinsky RJ . 1989. Neutrophil-mediated endothelial injury in haemolytic uraemic syndrome. Lancet 2 : 411 414.[PubMed] [CrossRef]
68. Fernandez GC,, Gomez SA,, Ramos MV,, Bentancor LV,, Fernandez-Brando RJ,, Landoni VI,, Lopez L,, Ramirez F,, Diaz M,, Alduncin M,, Grimoldi I,, Exeni R,, Isturiz MA,, Palermo MS . 2007. The functional state of neutrophils correlates with the severity of renal dysfunction in children with hemolytic uremic syndrome. Pediatr Res 61 : 123 128.[PubMed] [CrossRef]
69. Fitzpatrick MM,, Shah V,, Trompeter RS,, Dillon MJ,, Barratt TM . 1992. Interleukin-8 and polymorphoneutrophil leucocyte activation in hemolytic uremic syndrome of childhood. Kidney Int 42 : 951 956.[PubMed] [CrossRef]
70. Liu J,, He T,, He Y,, Zhang Z,, Akahoshi T,, Kondo H,, Zhong S . 2002. Prolongation of functional life-span of neutrophils by recombinant verotoxin 2. Chin Med J (Engl) 115 : 900 903.[PubMed]
71. Ge S,, Hertel B,, Emden SH,, Beneke J,, Menne J,, Haller H,, von Vietinghoff S . 2012. Microparticle generation and leucocyte death in Shiga toxin-mediated HUS. Nephrol Dial Transplant 27 : 2768 2775.[PubMed] [CrossRef]
72. Fernandez GC,, Lopez MF,, Gomez SA,, Ramos MV,, Bentancor LV,, Fernandez-Brando RJ,, Landoni VI,, Dran GI,, Meiss R,, Isturiz MA,, Palermo MS . 2006. Relevance of neutrophils in the murine model of haemolytic uraemic syndrome: mechanisms involved in Shiga toxin type 2-induced neutrophilia. Clin Exp Immunol 146 : 76 84.[PubMed] [CrossRef]
73. Fukuda MN,, Dell A,, Oates JE,, Wu P,, Klock JC,, Fukuda M . 1985. Structures of glycosphingolipids isolated from human granulocytes. The presence of a series of linear poly-N-acetyllactosaminylceramide and its significance in glycolipids of whole blood cells. J Biol Chem 260 : 1067 1082.[PubMed]
74. Arfilli V,, Carnicelli D,, Rocchi L,, Ricci F,, Pagliaro P,, Tazzari PL,, Brigotti M . 2010. Shiga toxin 1 and ricin A chain bind to human polymorphonuclear leucocytes through a common receptor. Biochem J 432 : 173 180.[PubMed] [CrossRef]
75. Geelen JM,, van der Velden TJ,, Te Loo DM,, Boerman OC,, van den Heuvel LP,, Monnens LA . 2007. Lack of specific binding of Shiga-like toxin (verocytotoxin) and non-specific interaction of Shiga-like toxin 2 antibody with human polymorphonuclear leucocytes. Nephrol Dial Transplant 22 : 749 755.[PubMed] [CrossRef]
76. Te Loo DM,, van Hinsbergh VW,, van den Heuvel LP,, Monnens LA . 2001. Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome. J Am Soc Nephrol 12 : 800 806.[PubMed]
77. Tazzari PL,, Ricci F,, Carnicelli D,, Caprioli A,, Tozzi AE,, Rizzoni G,, Conte R,, Brigotti M . 2004. Flow cytometry detection of Shiga toxins in the blood from children with hemolytic uremic syndrome. Cytometry B Clin Cytom 61 : 40 44.[PubMed] [CrossRef]
78. Ståhl AL,, Sartz L,, Nelsson A,, Békássy ZD,, Karpman D . 2009. Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS One 4 : e6990. [PubMed] [CrossRef]
79. Brigotti M,, Tazzari PL,, Ravanelli E,, Carnicelli D,, Rocchi L,, Arfilli V,, Scavia G,, Minelli F,, Ricci F,, Pagliaro P,, Ferretti AV,, Pecoraro C,, Paglialonga F,, Edefonti A,, Procaccino MA,, Tozzi AE,, Caprioli A . 2011. Clinical relevance of Shiga toxin concentrations in the blood of patients with hemolytic uremic syndrome. Pediatr Infect Dis J 30 : 486 490.[PubMed]
80. Szabady RL,, Lokuta MA,, Walters KB,, Huttenlocher A,, Welch RA . 2009. Modulation of neutrophil function by a secreted mucinase of Escherichia coli O157:H7. PLoS Pathog 5 : e1000320. [PubMed] [CrossRef]
81. Fernandez GC,, Ramos MV,, Gomez SA,, Dran GI,, Exeni R,, Alduncin M,, Grimoldi I,, Vallejo G,, Elias-Costa C,, Isturiz MA,, Palermo MS . 2005. Differential expression of function-related antigens on blood monocytes in children with hemolytic uremic syndrome. J Leukoc Biol 78 : 853 861.[PubMed] [CrossRef]
82. Ramos MV,, Fernandez GC,, Patey N,, Schierloh P,, Exeni R,, Grimoldi I,, Vallejo G,, Elias-Costa C,, Del Carmen Sasiain M,, Trachtman H,, Combadiere C,, Proulx F,, Palermo MS . 2007. Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome. Blood 109 : 2438 2445.[PubMed] [CrossRef]
83. van Setten PA,, Monnens LA,, Verstraten RG,, van den Heuvel LP,, van Hinsbergh VW . 1996. Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood 88 : 174 183.[PubMed]
84. Guessous F,, Marcinkiewicz M,, Polanowska-Grabowska R,, Keepers TR,, Obrig T,, Gear AR . 2005. Shiga toxin 2 and lipopolysaccharide cause monocytic THP-1 cells to release factors which activate platelet function. Thromb Haemost 94 : 1019 1027.[PubMed]
85. Murata K,, Higuchi T,, Takada K,, Oida K,, Horie S,, Ishii H . 2006. Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: possible signal transduction in tissue factor up-regulation. Biochim Biophys Acta 1762 : 835 843.[PubMed] [CrossRef]
86. Del Conde I,, Shrimpton CN,, Thiagarajan P,, Lopez JA . 2005. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106 : 1604 1611.[PubMed] [CrossRef]
87. Egorina EM,, Sovershaev MA,, Olsen JO,, Osterud B . 2008. Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer. Blood 111 : 1208 1216.[PubMed] [CrossRef]
88. Geelen JM,, van der Velden TJ,, van den Heuvel LP,, Monnens LA . 2007. Interactions of Shiga-like toxin with human peripheral blood monocytes. Pediatr Nephrol 22 : 1181 1187.[PubMed] [CrossRef]
89. Proulx F,, Seidman EG,, Karpman D . 2001. Pathogenesis of Shiga toxin-associated hemolytic uremic syndrome. Pediatr Res 50 : 163 171.[PubMed] [CrossRef]
90. Zoja C,, Buelli S,, Morigi M . 2010. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol 25 : 2231 2240.[PubMed] [CrossRef]
91. Fong JS,, Kaplan BS . 1982. Impairment of platelet aggregation in hemolytic uremic syndrome: evidence for platelet “exhaustion.” Blood 60 : 564 570.[PubMed]
92. Sassetti B,, Vizcarguenaga MI,, Zanaro NL,, Silva MV,, Kordich L,, Florentini L,, Diaz M,, Vitacco M,, Sanchez Avalos JC . 1999. Hemolytic uremic syndrome in children: platelet aggregation and membrane glycoproteins. J Pediatr Hematol Oncol 21 : 123 128.[PubMed] [CrossRef]
93. Galli M,, Grassi A,, Barbui T . 1996. Platelet-derived microvesicles in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Thromb Haemost 75 : 427 431.[PubMed]
94. Walters MD,, Levin M,, Smith C,, Nokes TJ,, Hardisty RM,, Dillon MJ,, Barratt TM . 1988. Intravascular platelet activation in the hemolytic uremic syndrome. Kidney Int 33 : 107 115.[PubMed] [CrossRef]
95. Keepers TR,, Psotka MA,, Gross LK,, Obrig TG . 2006. A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol 17 : 3404 3414.[PubMed] [CrossRef]
96. Cooling LL,, Walker KE,, Gille T,, Koerner TA . 1998. Shiga toxin binds human platelets via globotriaosylceramide (Pk antigen) and a novel platelet glycosphingolipid. Infect Immun 66 : 4355 4366.[PubMed]
97. Ghosh SA,, Polanowska-Grabowska RK,, Fujii J,, Obrig T,, Gear AR . 2004. Shiga toxin binds to activated platelets. J Thromb Haemost 2 : 499 506.[PubMed] [CrossRef]
98. Ståhl AL,, Svensson M,, Morgelin M,, Svanborg C,, Tarr PI,, Mooney JC,, Watkins SL,, Johnson R,, Karpman D . 2006. Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108 : 167 176.[PubMed] [CrossRef]
99. Karpman D,, Papadopoulou D,, Nilsson K,, Sjögren AC,, Mikaelsson C,, Lethagen S . 2001. Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97 : 3100 3108.[PubMed] [CrossRef]
100. Semple JW,, Italiano JE Jr,, Freedman J . 2011. Platelets and the immune continuum. Nat Rev Immunol 11 : 264 274.[PubMed] [CrossRef]
101. Moore KL,, Patel KD,, Bruehl RE,, Li F,, Johnson DA,, Lichenstein HS,, Cummings RD,, Bainton DF,, McEver RP . 1995. P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 128 : 661 671.[PubMed] [CrossRef]
102. Michelson AD,, Barnard MR,, Krueger LA,, Valeri CR,, Furman MI . 2001. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 104 : 1533 1537.[PubMed] [CrossRef]
103. Gear AR,, Camerini D . 2003. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 10 : 335 350.[PubMed] [CrossRef]
104. Shiraki R,, Inoue N,, Kawasaki S,, Takei A,, Kadotani M,, Ohnishi Y,, Ejiri J,, Kobayashi S,, Hirata K,, Kawashima S,, Yokoyama M . 2004. Expression of Toll-like receptors on human platelets. Thromb Res 113 : 379 385.[PubMed] [CrossRef]
105. Andonegui G,, Kerfoot SM,, McNagny K,, Ebbert KV,, Patel KD,, Kubes P . 2005. Platelets express functional Toll-like receptor-4. Blood 106 : 2417 2423.[PubMed] [CrossRef]
106. Aslam R,, Speck ER,, Kim M,, Crow AR,, Bang KW,, Nestel FP,, Ni H,, Lazarus AH,, Freedman J,, Semple JW . 2006. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107 : 637 641.[PubMed] [CrossRef]
107. Cicala C,, Santacroce C,, Itoh H,, Douglas GJ,, Page CP . 1997. A study on rat platelet responsiveness following intravenous endotoxin administration. Life Sci 60 : PL31 PL38.[PubMed]
108. Jayachandran M,, Brunn GJ,, Karnicki K,, Miller RS,, Owen WG,, Miller VM . 2007. In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk. J Appl Physiol 102 : 429 433.[PubMed] [CrossRef]
109. Scott T,, Owens MD . 2008. Thrombocytes respond to lipopolysaccharide through Toll-like receptor-4, and MAP kinase and NF-kappaB pathways leading to expression of interleukin-6 and cyclooxygenase-2 with production of prostaglandin E2. Mol Immunol 45 : 1001 1008.[PubMed] [CrossRef]
110. Elzey BD,, Tian J,, Jensen RJ,, Swanson AK,, Lees JR,, Lentz SR,, Stein CS,, Nieswandt B,, Wang Y,, Davidson BL,, Ratliff TL . 2003. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 19 : 9 19.[PubMed] [CrossRef]
111. Viisoreanu D,, Polanowska-Grabowska R,, Suttitanamongkol S,, Obrig TG,, Gear AR . 2000. Human platelet aggregation is not altered by Shiga toxins 1 or 2. Thromb Res 98 : 403 410.[CrossRef]
112. Gawaz M,, Neumann FJ,, Dickfeld T,, Koch W,, Laugwitz KL,, Adelsberger H,, Langenbrink K,, Page S,, Neumeier D,, Schomig A,, Brand K . 1998. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 98 : 1164 1171.[PubMed] [CrossRef]
113. Henn V,, Slupsky JR,, Grafe M,, Anagnostopoulos I,, Forster R,, Muller-Berghaus G,, Kroczek RA . 1998. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391 : 591 594.[PubMed] [CrossRef]
114. Hollenbaugh D,, Mischel-Petty N,, Edwards CP,, Simon JC,, Denfeld RW,, Kiener PA,, Aruffo A . 1995. Expression of functional CD40 by vascular endothelial cells. J Exp Med 182 : 33 40.[PubMed] [CrossRef]
115. Caprioli A,, Luzzi I,, Rosmini F,, Resti C,, Edefonti A,, Perfumo F,, Farina C,, Goglio A,, Gianviti A,, Rizzoni G . 1994. Community-wide outbreak of hemolytic-uremic syndrome associated with non-O157 verocytotoxin-producing Escherichia coli . J Infect Dis 169 : 208 211.[PubMed] [CrossRef]
116. Proulx F,, Seidman E,, Mariscalco MM,, Lee K,, Caroll S . 1999. Increased circulating levels of lipopolysaccharide binding protein in children with Escherichia coli O157:H7 hemorrhagic colitis and hemolytic uremic syndrome. Clin Diagn Lab Immunol 6 : 773. [PubMed]
117. Jerala R . 2007. Structural biology of the LPS recognition. Int J Med Microbiol 297 : 353 363.[PubMed] [CrossRef]
118. Valles PG,, Melechuck S,, Gonzalez A,, Manucha W,, Bocanegra V,, Valles R . 2012. Toll-like receptor 4 expression on circulating leucocytes in hemolytic uremic syndrome. Pediatr Nephrol 27 : 407 415.[PubMed] [CrossRef]
119. Kamitsuji H,, Nonami K,, Murakami T,, Ishikawa N,, Nakayama A,, Umeki Y . 2000. Elevated tissue factor circulating levels in children with hemolytic uremic syndrome caused by verotoxin-producing E. coli . Clin Nephrol 53 : 319 324.[PubMed]
120. Edgington TS,, Mackman N,, Brand K,, Ruf W . 1991. The structural biology of expression and function of tissue factor. Thromb Haemost 66 : 67 79.[PubMed]
121. Rao LV,, Rapaport SI,, Bajaj SP . 1986. Activation of human factor VII in the initiation of tissue factor-dependent coagulation. Blood 68 : 685 691.[PubMed]
122. Monroe DM,, Hoffman M . 2006. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 26 : 41 48.[PubMed] [CrossRef]
123. Camera M,, Frigerio M,, Toschi V,, Brambilla M,, Rossi F,, Cottell DC,, Maderna P,, Parolari A,, Bonzi R,, De Vincenti O,, Tremoli E . 2003. Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs. Arterioscler Thromb Vasc Biol 23 : 1690 1696.[PubMed] [CrossRef]
124. Schwertz H,, Tolley ND,, Foulks JM,, Denis MM,, Risenmay BW,, Buerke M,, Tilley RE,, Rondina MT,, Harris EM,, Kraiss LW,, Mackman N,, Zimmerman GA,, Weyrich AS . 2006. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 203 : 2433 2440.[PubMed] [CrossRef]
125. Panes O,, Matus V,, Saez CG,, Quiroga T,, Pereira J,, Mezzano D . 2007. Human platelets synthesize and express functional tissue factor. Blood 109 : 5242 5250.[PubMed] [CrossRef]
126. del Conde I,, Nabi F,, Tonda R,, Thiagarajan P,, Lopez JA,, Kleiman NS . 2005. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler Thromb Vasc Biol 25 : 1065 1070.[PubMed] [CrossRef]
127. Østerud B,, Olsen JO . 2013. Human platelets do not express tissue factor. Thromb Res 132 : 112 115.[PubMed] [CrossRef]
128. Bolande RP,, Kaplan BS . 1985. Experimental studies on the hemolytic-uremic syndrome. Nephron 39 : 228 236.[PubMed] [CrossRef]
129. Appiani AC,, Edefonti A,, Bettinelli A,, Cossu MM,, Paracchini ML,, Rossi E . 1982. The relationship between plasma levels of the factor VIII complex and platelet release products (beta-thromboglobulin and platelet factor 4) in children with the hemolytic-uremic syndrome. Clin Nephrol 17 : 195 199.[PubMed]
130. van de Kar NC,, van Hinsbergh VW,, Brommer EJ,, Monnens LA . 1994. The fibrinolytic system in the hemolytic uremic syndrome: in vivo and in vitro studies. Pediatr Res 36 : 257 264.[PubMed] [CrossRef]
131. Tsai HM,, Chandler WL,, Sarode R,, Hoffman R,, Jelacic S,, Habeeb RL,, Watkins SL,, Wong CS,, Williams GD,, Tarr PI . 2001. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res 49 : 653 659.[PubMed] [CrossRef]
132. Morigi M,, Galbusera M,, Binda E,, Imberti B,, Gastoldi S,, Remuzzi A,, Zoja C,, Remuzzi G . 2001. Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 98 : 1828 1835.[PubMed] [CrossRef]
133. Nolasco LH,, Turner NA,, Bernardo A,, Tao Z,, Cleary TG,, Dong JF,, Moake JL . 2005. Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106 : 4199 4209.[PubMed] [CrossRef]
134. Guessous F,, Marcinkiewicz M,, Polanowska-Grabowska R,, Kongkhum S,, Heatherly D,, Obrig T,, Gear AR . 2005. Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. Infect Immun 73 : 8306 8316.[PubMed] [CrossRef]
135. Furie B,, Furie BC . 2008. Mechanisms of thrombus formation. N Engl J Med 359 : 938 949.[PubMed] [CrossRef]
136. Nevard CH,, Jurd KM,, Lane DA,, Philippou H,, Haycock GB,, Hunt BJ . 1997. Activation of coagulation and fibrinolysis in childhood diarrhoea-associated haemolytic uraemic syndrome. Thromb Haemost 78 : 1450 1455.[PubMed]
137. Van Geet C,, Proesmans W,, Arnout J,, Vermylen J,, Declerck PJ . 1998. Activation of both coagulation and fibrinolysis in childhood hemolytic uremic syndrome. Kidney Int 54 : 1324 1330.[PubMed] [CrossRef]
138. Chandler WL,, Jelacic S,, Boster DR,, Ciol MA,, Williams GD,, Watkins SL,, Igarashi T,, Tarr PI . 2002. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med 346 : 23 32.[PubMed] [CrossRef]
139. Bergstein JM,, Riley M,, Bang NU . 1992. Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome. N Engl J Med 327 : 755 759.[PubMed] [CrossRef]
140. Chaisri U,, Nagata M,, Kurazono H,, Horie H,, Tongtawe P,, Hayashi H,, Watanabe T,, Tapchaisri P,, Chongsa-nguan M,, Chaicumpa W . 2001. Localization of Shiga toxins of enterohaemorrhagic Escherichia coli in kidneys of paediatric and geriatric patients with fatal haemolytic uraemic syndrome. Microb Pathog 31 : 59 67.[PubMed] [CrossRef]
141. Uchida H,, Kiyokawa N,, Horie H,, Fujimoto J,, Takeda T . 1999. The detection of Shiga toxins in the kidney of a patient with hemolytic uremic syndrome. Pediatr Res 45 : 133 137.[PubMed] [CrossRef]
142. Karpman D,, Håkansson A,, Perez MT,, Isaksson C,, Carlemalm E,, Caprioli A,, Svanborg C . 1998. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: in vivo and in vitro studies. Infect Immun 66 : 636 644.[PubMed]
143. Buteau C,, Proulx F,, Chaibou M,, Raymond D,, Clermont MJ,, Mariscalco MM,, Lebel MH,, Seidman E . 2000. Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome. Pediatr Infect Dis J 19 : 642 647.[PubMed] [CrossRef]
144. Salzman MB,, Ettenger RB,, Cherry JD . 1991. Leukocytosis in hemolytic-uremic syndrome. Pediatr Infect Dis J 10 : 470 471.[PubMed] [CrossRef]
145. Coad NA,, Marshall T,, Rowe B,, Taylor CM . 1991. Changes in the postenteropathic form of the hemolytic uremic syndrome in children. Clin Nephrol 35 : 10 16.[PubMed]
146. Inward CD,, Howie AJ,, Fitzpatrick MM,, Rafaat F,, Milford DV,, Taylor CM . 1997. Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. British Association for Paediatric Nephrology. Pediatr Nephrol 11 : 556 559.[PubMed] [CrossRef]
147. Roche JK,, Keepers TR,, Gross LK,, Seaner RM,, Obrig TG . 2007. CXCL1/KC and CXCL2/MIP-2 are critical effectors and potential targets for therapy of Escherichia coli O157:H7-associated renal inflammation. Am J Pathol 170 : 526 537.[PubMed] [CrossRef]
148. Keepers TR,, Gross LK,, Obrig TG . 2007. Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic-uremic syndrome. Infect Immun 75 : 1229 1236.[PubMed] [CrossRef]
149. Garcia A,, Marini RP,, Catalfamo JL,, Knox KA,, Schauer DB,, Rogers AB,, Fox JG . 2008. Intravenous Shiga toxin 2 promotes enteritis and renal injury characterized by polymorphonuclear leukocyte infiltration and thrombosis in Dutch Belted rabbits. Microbes Infect 10 : 650 656.[PubMed] [CrossRef]
150. Zoja C,, Angioletti S,, Donadelli R,, Zanchi C,, Tomasoni S,, Binda E,, Imberti B,, te Loo M,, Monnens L,, Remuzzi G,, Morigi M . 2002. Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-kappaB dependent up-regulation of IL-8 and MCP-1. Kidney Int 62 : 846 856.[PubMed] [CrossRef]
151. Zanchi C,, Zoja C,, Morigi M,, Valsecchi F,, Liu XY,, Rottoli D,, Locatelli M,, Buelli S,, Pezzotta A,, Mapelli P,, Geelen J,, Remuzzi G,, Hawiger J . 2008. Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. J Immunol 181 : 1460 1469.[PubMed] [CrossRef]
152. Morigi M,, Micheletti G,, Figliuzzi M,, Imberti B,, Karmali MA,, Remuzzi A,, Remuzzi G,, Zoja C . 1995. Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood 86 : 4553 4558.[PubMed]
153. Brigotti M,, Caprioli A,, Tozzi AE,, Tazzari PL,, Ricci F,, Conte R,, Carnicelli D,, Procaccino MA,, Minelli F,, Ferretti AV,, Paglialonga F,, Edefonti A,, Rizzoni G . 2006. Shiga toxins present in the gut and in the polymorphonuclear leukocytes circulating in the blood of children with hemolytic-uremic syndrome. J Clin Microbiol 44 : 313 317.[PubMed] [CrossRef]
154. Karpman D,, Manea M,, Vaziri-Sani F,, Ståhl AL,, Kristoffersson AC . 2006. Platelet activation in hemolytic uremic syndrome. Semin Thromb Hemost 32 : 128 145.[PubMed] [CrossRef]
155. Stearns-Kurosawa DJ,, Oh SY,, Cherla RP,, Lee MS,, Tesh VL,, Papin J,, Henderson J,, Kurosawa S . 2013. Distinct renal pathology and a chemotactic phenotype after enterohemorrhagic Escherichia coli Shiga toxins in non-human primate models of hemolytic uremic syndrome. Am J Pathol 182 : 1227 1238.[PubMed] [CrossRef]
156. Lopez EL,, Devoto S,, Fayad A,, Canepa C,, Morrow AL,, Cleary TG . 1992. Association between severity of gastrointestinal prodrome and long-term prognosis in classic hemolytic-uremic syndrome. J Pediatr 120 : 210 215.[CrossRef]
157. van Setten PA,, van Hinsbergh VW,, van den Heuvel LP,, Preyers F,, Dijkman HB,, Assmann KJ,, van der Velden TJ,, Monnens LA . 1998. Monocyte chemoattractant protein-1 and interleukin-8 levels in urine and serum of patents with hemolytic uremic syndrome. Pediatr Res 43 : 759 767.[PubMed] [CrossRef]
158. Decaluwe H,, Harrison LM,, Mariscalco MM,, Gendrel D,, Bohuon C,, Tesh VL,, Proulx F . 2006. Procalcitonin in children with Escherichia coli O157:H7 associated hemolytic uremic syndrome. Pediatr Res 59 : 579 583.[PubMed] [CrossRef]
159. Proulx F,, Toledano B,, Phan V,, Clermont MJ,, Mariscalco MM,, Seidman EG . 2002. Circulating granulocyte colony-stimulating factor, C-X-C, and C-C chemokines in children with Escherichia coli O157:H7 associated hemolytic uremic syndrome. Pediatr Res 52 : 928 934.[PubMed] [CrossRef]
160. Masri C,, Proulx F,, Toledano B,, Clermont MJ,, Mariscalco MM,, Seidman EG,, Carcillo J . 2000. Soluble Fas and soluble Fas-ligand in children with Escherichia coli O157:H7-associated hemolytic uremic syndrome. Am J Kidney Dis 36 : 687 694.[PubMed] [CrossRef]
161. Proulx F,, Turgeon JP,, Litalien C,, Mariscalco MM,, Robitaille P,, Seidman E . 1998. Inflammatory mediators in Escherichia coli O157:H7 hemorrhagic colitis and hemolytic-uremic syndrome. Pediatr Infect Dis J 17 : 899 904.[PubMed] [CrossRef]
162. Litalien C,, Proulx F,, Mariscalco MM,, Robitaille P,, Turgeon JP,, Orrbine E,, Rowe PC,, McLaine PN,, Seidman E . 1999. Circulating inflammatory cytokine levels in hemolytic uremic syndrome. Pediatr Nephrol 13 : 840 845.[PubMed] [CrossRef]
163. van de Kar NC,, Sauerwein RW,, Demacker PN,, Grau GE,, van Hinsbergh VW,, Monnens LA . 1995. Plasma cytokine levels in hemolytic uremic syndrome. Nephron 71 : 309 313.[PubMed] [CrossRef]
164. Karpman D,, Andreasson A,, Thysell H,, Kaplan BS,, Svanborg C . 1995. Cytokines in childhood hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Pediatr Nephrol 9 : 694 699.[PubMed] [CrossRef]
165. Proulx F,, Litalien C,, Turgeon JP,, Mariscalco MM,, Seidman E . 2000. Circulating levels of transforming growth factor-beta1 and lymphokines among children with hemolytic uremic syndrome. Am J Kidney Dis 35 : 29 34.[PubMed] [CrossRef]
166. Inward CD,, Varagunam M,, Adu D,, Milford DV,, Taylor CM . 1997. Cytokines in haemolytic uraemic syndrome associated with verocytotoxin-producing Escherichia coli infection. Arch Dis Child 77 : 145 147.[PubMed] [CrossRef]
167. Inward CD,, Pall AA,, Adu D,, Milford DV,, Taylor CM . 1995. Soluble circulating cell adhesion molecules in haemolytic uraemic syndrome. Pediatr Nephrol 9 : 574 578.[PubMed] [CrossRef]
168. Murata A,, Shimazu T,, Yamamoto T,, Taenaka N,, Nagayama K,, Honda T,, Sugimoto H,, Monden M,, Matsuura N,, Okada S . 1998. Profiles of circulating inflammatory- and anti-inflammatory cytokines in patients with hemolytic uremic syndrome due to E. coli O157 infection. Cytokine 10 : 544 548.[PubMed] [CrossRef]
169. Yamamoto T,, Nagayama K,, Satomura K,, Honda T,, Okada S . 2000. Increased serum IL-10 and endothelin levels in hemolytic uremic syndrome caused by Escherichia coli O157. Nephron 84 : 326 332.[PubMed] [CrossRef]
170. Lopez EL,, Contrini MM,, Devoto S,, de Rosa MF,, Grana MG,, Genero MH,, Canepa C,, Gomez HF,, Cleary TG . 1995. Tumor necrosis factor concentrations in hemolytic uremic syndrome patients and children with bloody diarrhea in Argentina. Pediatr Infect Dis J 14 : 594 598.[PubMed] [CrossRef]
171. Nevard CH,, Blann AD,, Jurd KM,, Haycock GB,, Hunt BJ . 1999. Markers of endothelial cell activation and injury in childhood haemolytic uraemic syndrome. Pediatr Nephrol 13 : 487 492.[PubMed] [CrossRef]
172. Caletti MG,, Balestracci A,, Roy AH . 2010. Levels of urinary transforming growth factor beta-1 in children with D+ hemolytic uremic syndrome. Pediatr Nephrol 25 : 1177 1180.[PubMed] [CrossRef]
173. Bhowmik D . 2001. Elevated tissue factor levels in children with hemolytic uremic syndrome. Clin Nephrol 55 : 262. [PubMed]
174. Petruzziello-Pellegrini TN,, Yuen DA,, Page AV,, Patel S,, Soltyk AM,, Matouk CC,, Wong DK,, Turgeon PJ,, Fish JE,, Ho JJ,, Steer BM,, Khajoee V,, Tigdi J,, Lee WL,, Motto DG,, Advani A,, Gilbert RE,, Karumanchi SA,, Robinson LA,, Tarr PI,, Liles WC,, Brunton JL,, Marsden PA . 2012. The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice. J Clin Invest 122 : 759 776.[PubMed] [CrossRef]
175. Louise CB,, Obrig TG . 1991. Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor alpha on human vascular endothelial cells in vitro. Infect Immun 59 : 4173 4179.[PubMed]
176. Keusch GT,, Acheson DW,, Aaldering L,, Erban J,, Jacewicz MS . 1996. Comparison of the effects of Shiga-like toxin 1 on cytokine- and butyrate-treated human umbilical and saphenous vein endothelial cells. J Infect Dis 173 : 1164 1170.[PubMed] [CrossRef]
177. van Setten PA,, van Hinsbergh VW,, van der Velden TJ,, van de Kar NC,, Vermeer M,, Mahan JD,, Assmann KJ,, van den Heuvel LP,, Monnens LA . 1997. Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 51 : 1245 1256.[PubMed] [CrossRef]
178. van de Kar NC,, Monnens LA,, Karmali MA,, van Hinsbergh VW . 1992. Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: implications for the pathogenesis of the hemolytic uremic syndrome. Blood 80 : 2755 2764.[PubMed]
179. Louise CB,, Obrig TG . 1992. Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of shiga toxin and lipopolysaccharide (endotoxin) on human vascular endothelial cells in vitro. Infect Immun 60 : 1536 1543.[PubMed]
180. Kaye SA,, Louise CB,, Boyd B,, Lingwood CA,, Obrig TG . 1993. Shiga toxin-associated hemolytic uremic syndrome: interleukin-1 beta enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro. Infect Immun 61 : 3886 3891.[PubMed]
181. Isogai E,, Isogai H,, Kimura K,, Hayashi S,, Kubota T,, Fujii N,, Takeshi K . 1998. Role of tumor necrosis factor alpha in gnotobiotic mice infected with an Escherichia coli O157:H7 strain. Infect Immun 66 : 197 202.[PubMed]
182. Harel Y,, Silva M,, Giroir B,, Weinberg A,, Cleary TB,, Beutler B . 1993. A reporter transgene indicates renal-specific induction of tumor necrosis factor (TNF) by Shiga-like toxin. Possible involvement of TNF in hemolytic uremic syndrome. J Clin Invest 92 : 2110 2116.[PubMed] [CrossRef]
183. Lentz EK,, Cherla RP,, Jaspers V,, Weeks BR,, Tesh VL . 2010. Role of tumor necrosis factor alpha in disease using a mouse model of Shiga toxin-mediated renal damage. Infect Immun 78 : 3689 3699.[PubMed] [CrossRef]
184. Wolski VM,, Soltyk AM,, Brunton JL . 2002. Tumour necrosis factor alpha is not an essential component of verotoxin 1-induced toxicity in mice. Microb Pathog 32 : 263 271.[PubMed] [CrossRef]
185. Hughes AK,, Stricklett PK,, Kohan DE . 1998. Shiga toxin-1 regulation of cytokine production by human proximal tubule cells. Kidney Int 54 : 1093 1106.[PubMed] [CrossRef]
186. Nakamura A,, Johns EJ,, Imaizumi A,, Yanagawa Y,, Kohsaka T . 2001. Activation of beta(2)-adrenoceptor prevents shiga toxin 2-induced TNF-alpha gene transcription. J Am Soc Nephrol 12 : 2288 2299.[PubMed]
187. Taylor FB Jr,, Tesh VL,, DeBault L,, Li A,, Chang AC,, Kosanke SD,, Pysher TJ,, Siegler RL . 1999. Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1. Am J Pathol